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Here, we demonstrate that Ins\/BBR exerts superior efficacy compared with single treatments by targeting multiple pathogenic pathways in PCOS. In a DHEA+HFD\u2010induced mouse model, Ins\/BBR restored systemic sex steroid balance, normalized LH\/FSH ratio, and improved estrous cyclicity. It also reduced ovarian cysts and enhanced fertility, accompanied by partial normalization of steroidogenic enzyme expression. At the cellular level, Ins\/BBR alleviated mitochondrial defects and broadly reprogrammed metabolic landscape in granulosa cells, in specific, restoring nucleotide pools and amino acid turnover and preventing abnormal long\u2010chain fatty acid accumulation. Together, these findings provide preclinical evidence that Ins\/BBR acts through coordinated endocrine, ovarian and metabolic mechanisms, supporting its promise as a safe and effective therapeutic strategy for PCOS.<\/jats:p>","DOI":"10.1111\/cpr.70188","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:58:57Z","timestamp":1772989137000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inositol and Berberine Synergistically Reprogram Endocrine and Ovarian Metabolism in Polycystic Ovary Syndrome"],"prefix":"10.1111","volume":"59","author":[{"given":"Juan","family":"Ge","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4697-6905","authenticated-orcid":false,"given":"Yilong","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Nanjing BioDe Biotechnology co., Ltd.  Nanjing China"},{"name":"Chinese Medicine Research Institute, Engineering Research Center of Modern Preparation Technology of Traditional Chinese Medicine, Ministry of Education Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guorui","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences Nanjing Medical University  Nanjing 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